Parathyroid hormone related peptide (hereinafter referred to as “PTHrP”) is a peptide discovered as a humoral factor produced by tumor cells in hypercalcemia in association with a malignant tumor. Further, PTHrP causes neoplastic hypercalcemia (Humoral hypercalcemia of malignancy; hereinafter referred to as “HHM”) by promoting bone resorption by osteoclast and calcium reabsorption in renal tubules.
It has been reported that PTHrP is produced not only in various neoplastic tissues but also in a wide variety of normal tissues throughout ontogeny including skin, central nerves, womb, placenta, mammary gland during breastfeeding, thyroid gland, parathyroid gland, adrenal gland, liver, kidney and bladder (see, for example, Non-patent Documents 1 and 2).
PTHrP has physiological effects such as: control of differentiation and proliferation of cells, relaxation of smooth muscle, promotion of transplacental calcium transportation, promotion of apoptosis and causes clinical conditions such as hypercalcemia represented by HHM, hypophosphatemia. These effects of PTHrP are exhibited through the binding of PTHrP to PTH/PTHrP receptors mainly found in bone and kidney, which activates plural intracellular signaling systems.
Meanwhile, the present inventors have already reported that PTHrP controls differentiation of cartilage cells from pre-hypertrophy stage to hypertrophy stage. As for the differentiation regulation of cartilage cells, participation of feedback between intracellular signaling of PTHrP and Indian hedgehog is suggested, but the mechanism through which ATTACHMENT A PTHrP effects on bone formation has not yet been elucidated (see, for example, Non-patent Documents 3 and 4).
Many of the bones constituting the framework of a vertebrate animal are built by the ossification process called enchondral bone formation. In the enchondral bone formation, proliferated cartilage cells, while continuing differentiation, build an environment which facilitates bone to be formed, and finally they die and are replaced by bone. Apoptosis is proposed as a mechanism of the extinction of the cartilage cells in the enchondral bone formation (see, for example, Non-patent Documents 5 and 6).
Apoptosis is controlled by the expression ratio of cell death inhibiting factor Bcl-2 and cell death inducing factor Bax in some cell systems. That is, whether a cell will be alive or dead is determined by the ratio of Bcl-2 and Bax in the cell. It has been revealed recently that the Bcl-2 gene is located downstream of the PTHrP gene in the signaling path which controls maturity of cartilage cells and that PTHrP increases expression of Bcl-2 (see, for example, Non-patent Document 7).
Meanwhile, it has been reported that both the expressions of PTHrP and Bcl-2 are high in chondrosarcoma cells (see, for example, Non-patent Documents 8 and 9). Chondrosarcoma is a chondrogenetic malignant tumor and is the second most bone tumor after osteosarcoma. Because it has a bad response to chemotherapy or radiotherapy, it is chiefly treated by surgical excision. However, the prognosis of chondrosarcoma is not good in mesenchymal dedifferentiated chondrosarcoma in the grade III while it is comparatively good (65% of five-year probability of survival) in the case of Grades I and II. Accordingly, a new medical treatment method of improving the prognosis of chondrosarcoma is desired.
On the other hand, it is already known that the antibody to PTHrP (hereinafter referred to as “anti-PTHrP antibody”) is useful for treating HHM or cachexia resulting from PTHrP (see, for example, Patent Document 1 and Non-patent Document 10) and preventing progress of bone metastasis of cancer. However, the effect of PTHrP on chondroma, chondrosarcoma and the like has not been scarcely clarified and in addition, there is no report until now indicating the use of PTHrP or anti-PTHrP antibody in the treatment of chondroma or chondrosarcoma.
Patent Document 1:
JP Patent Publication (Kokai) No. 11-80025 A (1999)
Non-Patent Document 1:
Burtis, W. J., Clin. Chem. 1992; 38: p 2171-2183
Non-Patent Document 2:
Stewart, A. F. & Broadus, A. E. J., Clin. Endocrinol. 1991; 71: p 1410-1414
Non-Patent Document 3:
Nakase T. et al., Histochem. Cell Biol. 2001; 116: p 277-284
Non-Patent Document 4:
Suda N. et al., Oral Dis. 1997; 3: p 229-231
Non-Patent Document 5:
Famum C. E., et al., Am. J. Anat. 1989; 186: p 346-358
Non-Patent Document 6:
Lewinson D. et al., Anat. Rec. 1992; 233: p 504-514
Non-Patent Document 7:
Amling M., et al., J. Cell Biol. 1997; 136: p 205-213
Non-Patent Document 8:
Amling M. et al., Verh. Dtsch. Ges. Pathol. 1998; 82: p 160-169
Non-Patent Document 9:
Bovee J. V., et al., Lab. Invest. 2000; 80: p 1925-1934 Non-patent Document 10:
Sato et al., J. bone & Mine. Res. 1993; 8: p 849-860